Each one of us carries trillions and trillions of 'bugs', as Jeroen Raes (Group Leader at Bioinformatics and (eco-)systems biology lab, VIB/VUB/KU Leuven) likes to call them —micro-organisms that live in our bodies and make up the so-called microbiome, or gut flora. While these microbes have been linked to different diseases, information about which factors in a healthy individual’s diet and lifestyle affect the microbiome has remained elusive. What is the potential of the microbiota as a diagnostic solution at this time? Can we manipulate it to prevent diseases and use it to influence drug sensitivity? What are the challenges in the microbiomics field? Will we be able to develop targeted, even personalized probiotics? Is there a hype surrounding microbiomics that the public, scientists and communicators must take into account when evaluating its recent advances and future possibilities?
Bioinformatics revolutionized microbiology
Raes is a leading microbiome researcher who specializes in computational metagenomics analysis. He became involved in some very early microbiome work at Peer Bork’s lab (The European Molecular Biology Laboratory) in Heidelberg, Germany. Raes says leaving Belgium to do research in a more advanced lab abroad was a major stepping stone for his career.
If you want to do cutting-edge science, you have to go to a cutting-edge lab.
“The best advice I can give to any PhD student is going to the best lab in the world that you can imagine,” shares Raes. “If you want to do cutting-edge science, you have to go to a cutting-edge lab. You might have to go outside Belgium."
“In the beginning it was crazy. In the period 2005–2015, the microbial field was exploding and anything that you did was new. That was extremely exciting; we were doing real discovery science,” continues Raes. After his highly successful fellowship in Bork’s lab, Raes returned to Belgium with unique expertise in computational eco-systems biology. “We started with pure bioinformatics. However, in the last five years, we have become a lab that balances its activities between in vitro tests and computational technologies. We solved the basic analysis of metagenomics data five years ago. Most of it is done. Now comes the interesting part — how can we use this in the clinic?”
“Sequencing and metagenomics revolutionized the microbiology field 10 years ago,” Raes says. “We could massively analyze the DNA of many samples and understand the whole bacterial ecosystem, thanks to bioinformatics. Metagenomics data is like a jigsaw puzzle of which you have lost 70–80% of the pieces. We had to puzzle it all together without having the majority of the pieces. This requires complex bioinformatics, and in the beginning we spent a lot of time developing techniques to analyze this data. The urgent need for bioinformatics development is a bit less now. What we ultimately want to do is to predict how the microbiome system is going to behave if you give drugs to a patient, and how that will affect the drug itself.”
Taking two steps forward and one back
We actually show that quite a number of previously suggested targets of diagnostic marker species are associated with non-disease states as well.
Raes is also an initiator of the Flemish Gut Flora Project, which provided the first population-based microbiome characterization of gut flora variation among healthy individuals. For the sake of proper microbiome-centered clinical studies, it is essential to first define what a 'normal' gut flora means. The study, led by Raes and recently published in the leading scientific journal Science, shows that many factors, such as transit time, health, diet and medication are correlated with microbiome diversity and composition. Currently, the microbiome is a hot target for diagnostic and disease prevention purposes, but the new data from the Raes lab raise the question of how realistic this actually is at this time.
For instance, microbiotic markers have been suggested for Parkinson’s disease, but I am almost 100% certain that these are not markers for Parkinson’s, but for intestinal transit time.
“The world has been rushing forward, looking for clinical solutions and diagnostic markers, but has failed thus far to map the natural variability of all factors influencing the microbiome. If you want to go towards diagnostic markers or identify targets, you have to make sure that the signal you see is the right one. Now we actually show that quite a number of previously suggested targets of diagnostic marker species are associated with non-disease states as well,” comments Raes. “There is a real need to go back to earlier clinical studies and validate whether the results were not influenced by the factors that we identified. This is how things go — you take two steps forward, and then you take one back, but slowly you move forward. I think we did one of those steps back. For instance, microbiotic markers have been suggested for Parkinson’s disease, but I am almost 100% certain that these are not markers for Parkinson’s, but for intestinal transit time. Because Parkinson’s disease patients are constipated, we are basically measuring constipation and not Parkinson’s. This is nice, but for measuring constipation you don't need fancy microbiome techniques, right?"
It is really important that the new data are taken into account, and I hope our Science paper shows that this is the only way to come to proper and reliable microbiome-based diagnostics.
A promising future for microbiota in preventive and therapeutic medicine
Probiotics are living organisms that — when administered in proper amounts — bring us health benefits. Several studies suggest that probiotics improve our intestinal and immune function, but can probiotics really be used to prevent disease?
“There is potential, but it is very challenging work,” Raes says. “It requires long-term studies with patients at risk for getting a certain disease. Right now, it is very difficult to say what type of dietary intervention should be done to push the microbiota in a certain direction. So far, the techniques are rather crude, and they ultimately should be replaced by something defined — a cocktail, a mixture of bacteria. To think of prevention in terms of targeted probiotics, we have to find the organisms that are associated with the onset of the disease. Only then we can use microbiota not only as a diagnostic, but also as a drug. It is still in the early stage, but I see a lot of development happening and also pharma moving in. I strongly believe that we will develop a next generation of targeted probiotics for different diseases, possibly even tailored to every patient’s needs.”
People should not forget that our gut microbiota is a real pharmacy we have down there.
An increasing number of studies show that the microbiota also affects the pharmacokinetics of drugs and immunotherapy. “This is a very important area for pharma,” Raes says. “It might explain some of the differential response — efficacy and side effects — that drugs have in clinical trials. It is coming on people’s radars, but I believe the effect is much stronger than what is believed now.”
Patience, patience, patience
“The potential in the microbiome field is gigantic, but the hype is also gigantic,” warns Raes. “The public is so excited about this, but we cannot forget that the scientific and drug development process is slow. People are hoping to see very quick results in no time, and I am not sure that this is realistic. Still, there will be strong implications in terms of drugs and diagnostics coming out of this field — I am absolutely convinced — but probably not in every area that is promised now.”
People should just be patient. Pharma is coming in and investing in microbiota work at the moment. That's a good sign.”
Raes concludes: “We are moving out of the exploratory phase, which was relatively fast. Now we are entering the validation phase with the intervention studies, the in vitro work and the animal models. Our lab is spending a lot of time on this: We combine the power of omics with in vitro and in vivo follow-up studies. This combination will show the true strength of the microbiome field. And pharma will also impose its rigor and its way of working. This will also help to mature the field, to take away some of the hype and replace it with hard facts and properly controlled studies.”
Falony, Gwen, et al. Population-level analysis of gut microbiome variation. Science 352.6285 (2016): 560-564.